Azetidinone compound and process for preparation thereof

ABSTRACT

There is disclosed an azetidinone compound of the formula [I]: ##STR1## wherein Ring B is a benzene ring which may have substituent(s), R 1  is a hydroxy-substituted lower alkyl group which may have substituent(s), X is oxygen atom and the like, Y is oxygen atom and the like, and Z is a methylene group which may have substituent(s), which is useful as a synthetic intermediate of the 1β-methylcarbapenem-type antibacterial agent.

This invention relates to a novel compound useful as a syntheticintermediate of a 1β-methylcarbapenem derivative having an antibacterialactivity, a process for preparation thereof and a use thererof.

BACKGROUND OF THE INVENTION

1β-Methylcarbapenem derivatives have been of great interest for theirexcellent antibacterial activities against a wide range ofmicroorganisms including Gram positive and Gram negative bacteria,especially against Cephem-resistant bacteria, and their excellentstabilities in the human bodies. Said 1β-methylcarbapenem derivativeshave been synthesized by various processes up to now. In theseprocesses, the following three kinds of compounds have been known as theimportant synthetic intermediates:

a) an azetidinone compound having a 1'-β-methyl group at the 4-positionof the azetidinone skeleton, i.e., a compound of the formula [A]:##STR2## wherein R^(a) is a hydroxy-substituted lower alkyl group whichmay be protected,

b) a 1β-methyl-2-oxocarbapenem compound of the formula [B]: ##STR3##wherein R^(b) is a hydrogen atom or an ester residue, and R^(a) is thesame as defined above and

c) a reactive derivative of the compound [B], i.e., a compound of theformula [C]: ##STR4## wherein a group of the formula: --OA^(a) is anesterified hydroxy group, and R^(a) and R^(b) are the same as definedabove.

As for a process for preparing these synthetic intermediates, there hasbeen known a process which comprises the steps of:

1) removing 1'-hydrogen atom of the acetic acid moiety located at the4-position of the compound of the following formula: ##STR5## by using astrong base, 2) introducing methyl group to the product,

3) hydrolyzing the product to give the compound [A] in which R^(a) is1-t-butyldimethylsilyloxyethyl group,

4) subjecting the product to carbon atom increasing reaction,

5) subjecting the product to diazotization,

6) subjecting the product to intramolecular cyclization to give thecompound [B] in which R^(a) is 1-hydroxyethyl group and R^(b) isp-nitrobenzyl group, and then

7) subjecting the product to esterification to obtain the correspondingcompound [C] [Heterocycles Vol. 21 p29 (1984)].

However, the above process is unsatisfactory in that the yield of thecompound having the 1'-methyl group with β-configuration which shows anexcellent pharmacological activity is low, because in preparing thecompound [A] by the above process, said process is not a stereoselectivesynthetic process and the mixture of the compound [A] having the1'-methyl group with α-configuration and β-configuration is obtained. Inrecent years, therefore, various processes for stereoselectivelypreparing the compounds [A], [B] and [C] have been widely investigatedand a typical process includes those utilizing the Aldol-type reactionor the Reformatsky-type reaction.

As for the process utilizing the Aldol-type reaction, for example,Japanese Patent Publication (unexamined) No. 252786 of 1987 discloses aprocess for the preparation of the compound [A] in which R^(a) ist-butyldimethylsilyloxyethyl group, which comprises reacting a compoundof the formula [D]: ##STR6## with a propionamide compound of theformula: ##STR7## in the presence of dibutylboron triflate to give acompound of the formula: ##STR8## and then hydrolyzing the product.

Further, Japanese Patent Publication (unexamined) No. 284176 of 1988discloses a process for the preparation of the compounds [B] and [C],which comprises reacting the compound [D] with a compound of theformula: ##STR9## in the presence of tin triflate to give a compound ofthe formula: ##STR10## reacting the product with a compound of theformula: ##STR11## in the presence of imidazole, subjecting the productto diazotization, and then converting the product into the compound [B]or [C].

Moreover, Japanese Patent Publication (unexamined) Nos. 77384 of 1987,169781 of 1987, 246550 of 1987 and 292269 of 1990 disclose the processesusing the following compound instead of the above propionamide compound.##STR12##

However, although such Aldol-type reactions can introduce the β-methylgroup stereoselectively, the processes are still unsatisfactory for theindustrial scale production because expensive tin triflate or borontriflate must be used as a reagent in those reactions.

On the other hand, as for the process utilizing the Reformatsky-typereaction, for example, Japanese Patent Publication (unexamined) No.178262 of 1990 discloses a process for the preparation of the compound[B] or [C], which comprises reacting the compound [D] with anα-bromopropionamide compound of the formula: ##STR13## wherein Tr istriphenylmethyl group, in the presence of zinc to give a compound of theformula [E]: ##STR14## wherein Tr is the same as defined above,hydrolyzing the product to give the compound [A] and then convening theproduct into the compound [B] or [C]. Further, Japanese PatentPublication (unexamined) Nos. 10765 of and 188662 of 1988 disclose theprocesses using the following compound instead of the aboveα-bromopropionamide compound. ##STR15##

However, the process utilizing the Reformatsky-type reaction has somedefects in that β-methyl group can not be introduced stereoselectivelyor in that it is difficult to synthesize the α-bromopropionic acidcompound. Moreover, in order to convert the β-methyl group-introducedproduct into the compound [B] or [C], it is necessary to once eliminatethe group of the following formula: ##STR16## from said product and thenactivate the resulting compound by chemical modification, for example,by introducing a group which is suitable for the intramolecularcyclization.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a novel azetidinonecompound useful as a synthetic intermediate of a 1β-methylcarbapenemderivative having an antibacterial activity. Another object is toprovide a novel synthetic intermediate which can be converted into notonly the compound [A] by hydrolysis but also the 1β-methylcarbapenemcompound by introducing a protected or unprotected carboxymethyl groupto N-position thereof, and then subjecting the product to intramolecularcyclization. Another object is to provide a novel process for preparingthe above synthetic intermediate stereoselectively by making use of theReformatsky reaction. Still another object is to provide a novel processfor preparing a 1β-methylcarbapenem derivative or an intermediatethereof using the above synthetic intermediate. These and other objectsand advantages of the invention will be apparent to those skilled in theart from the following description.

DETAILED DESCRIPTION OF THE INVENTION

As a result of various investigations, the inventors of the presentinvention have found that when an α-halopropionamide compound of theformula [II]: ##STR17## wherein Ring B is a benzene ring which may havesubstituent(s), X is oxygen atom or sulfur atom, Y is oxygen atom,sulfur atom, methylene group or an imino group which may havesubstituent(s), Z is a methylene group which may have substituent(s),and L⁰ is a halogen atom, is used as one of the starting compounds ofthe Reformatsky-type reaction, β-methyl group can be introducedstereoselectively, and the product thus obtained has excellent featuresas the synthetic intermediate of 1β-methylcarbapenem derivatives.

Thus, this invention relates to an azetidinone compound of the formula[I]: ##STR18## wherein R¹ is a hydroxy-substituted lower alkyl groupwhich may be protected, and other symbols are the same as defined above,or a salt thereof, a process for preparation thereof and a use thereof.The compound [I] of the present invention is structurally quitedifferent from the above-mentioned known compound in that the amidomoiety (hereinafter referred to as "supporting group") of the compound[I] of the present invention is the benzene ring-condensed 6-memberedheterocyclic group, while the known supporting group is the 5-memberedheterocyclic groups such as thiazolidine or oxazolidine. In the presentinvention, any group having partial structure of the formula: ##STR19##wherein symbols are the same as defined above, can be used as thesupporting group of the present invention, and therefore, when Ring Band/or Z has (have) substituents, said substituents may be any which donot disadvantageously affect the reaction.

Examples of the substituent on Ring B include a halogen atom, a loweralkyl group, a lower alkoxy group, an aryl group and the like, and thebenzene ring may have one to four substituent(s) which is (are) the sameor different.

Examples of R¹ include a 1-hydroxyethyl group which may be protected,the protecting group of hydroxy group including any group which is usedconventionally as a protecting group of hydroxy group. Specific examplesof the protecting group of hydroxy group include a lower alkoxy-carbonylgroup, a halogeno-lower alkoxy-carbonyl group, a lower alkyl groupsubstituted by a pheny group which may have substituent(s) (e.g., abenzyl group which may be substituted by nitro group or a lower alkoxygroup), a tri-lower alkylsilyl group, a lower alkoxy-carbonyl groupsubstituted by a pheny group which may have substituent(s) (e.g., abenzyloxycarbonyl group which may be substituted by nitro group or alower alkoxy group).

Examples of the substituent on the imino group (Y) include a lower alkylgroup, an acyl group, an aralkyloxycarbonyl group and the like.

Examples of the substituent on the methylene group (Z) include a C₃₋₇alkylene group which may have substituent(s), a C₁₋₂₀ alkyl group whichmay have substituent(s), a C₄₋₇ cycloalkyl group which may havesubstituent(s), an aryl group, an aralkyl group, a heterocyclic groupand the like, and one to two substituent(s) which are the same ordifferent may be substituted on the methylene group.

Among the above, substituents on Ring B, Y and/or Z, specific examplesof the acyl group include a lower alkanoyl group, a lower alkoxycarbonylgroup, a substituted or unsubstituted phenylcarbonyl group or asubstituted or unsubstituted phenyl-lower alkoxycarbonyl group; those ofan aryl group include a substituted or unsubstituted phenyl group; thoseof an aralkyl group include a lower alkyl group substituted by asubstituted or unsubstituted phenyl group; and those of a heterocyclicgroup include a substituted or unsubstituted 4- to 7-memberedheterocyclic group containing oxygen atom, nitrogen atom or sulfur atomas a hetero atom (e.g., furyl group, pyrrolyl group, thienyl group).

Further, examples of the substituent on the above alkylene moiety, alkylmoiety, cycloalkyl moiety, phenyl moiety and heterocyclic moiety includea lower alkyl group, a lower alkoxy group, a halogen atom and an aminogroup which may be protected. As a protecting group of an amino group,any group which is conventionally used as a protecting group of theamino group in the field of Peptide Chemistry may be used.

Among these compounds [I], preferred compounds are those of the formula[I] wherein the 3-position of the azetidinone skeleton has Sconfiguration, Ring B is a benzene ring which may be substituted by ahalogen atom, a lower alkyl group or a lower alkoxy group, Y is oxygenatom, sulfur atom, methylene group or an imino group substituted by alower alkyl group, and Z is a methylene group which may be substitutedby one to two group(s) selected from a group consisting of a C₃₋₇alkylene group, a C₁₋₂₀ alkyl group and an aralkyl group.

Among them, more preferred compounds are those of the formula [I]wherein Ring B is an unsubstituted benzene ring, X is oxygen atom, Y isoxygen atom, and Z is a methylene group substituted by a C₃₋₇ alkylenegroup, a methylene group substituted by a di- C₁₋₂₀ alkyl group or amethylene group substituted by a di-(phenyl-lower alkyl)group.

Another group of more preferred compounds are those of the formula [I]wherein a substituent of Z is a bulky group such as a C₄₋₇ alkylenegroup, a C₄₋₂₀ alkyl group, a phenyl-lower alkyl group and the like.

Among them, most preferred compounds are those of the formula [I]wherein Z is pentamethylene-substituted methylene group (i.e.,cyclohexylidene group) or dibutyl-substituted methylene group.

When Z has one substituent or different two substituents, the compound[I] may exist in the form of two optical isomers and this inventionincludes these optical isomers and a mixture thereof.

Examples of a salt of the azetidinone compound [I] include an inorganicacid addition salt such as hydrochloride, hydrobromide, sulfate and thelike, and an organic acid addition salt such as acetate, oxalate,tartrate, fumarate, maleate, benzenesulfonate and the like.

According to the present invention, the azetidinone compound [I] can beprepared by reacting an α-halopropionamide compound [II] or a saltthereof with a compound of the formula [III]: ##STR20## wherein L ¹ is aleaving group, and R ¹ is the same as defined above.

The reaction of the α-halopropionamide compound [II] with the compound[III] can be preferably carried out in an appropriate solvent in thepresence of a metal compound which is used in the Grignard-typereaction, especially a metal compound which suitably forms a chelatebetween the compounds [III] and [III]. Examples of such metal compoundincludes zinc, magnesium, magnesium-magnesium bromide, tin, zinc-coppercouple, zinc chloride-lithium naphthylide, lithium and aluminum. Amongthem, preferred examples are zinc and magnesium. As the leaving group (L¹), any leaving group which can be easily replaced by a nucleophilicagent can be used. Particularly, any leaving group, which can easilyseparate from the compound [III] together with the halogen atom (L⁰) ofthe α-halopropionamide compound [II] and then a carbon-carbon bond canbe formed, may be used. Examples of such groups include an acyloxygroup, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, a loweralkylsulfonyl group, an arylsulfonyl group, an arylthio group and ahalogen atom. Among them, an acyloxy group is preferred. As the solvent,any inert solvent can be used. For example, tetrahydrofuran, toluene,xylene, dimethoxyethane, dimethylformamide,dimethylsulfoxide and thelike are preferably used.

The α-halopropionamide compound [II] is used in an amount of 1 to 3moles, preferably 1.3 to 1.7 moles, per one mole of the compound [III].And the metal compound (e.g., zinc, magnesium) is used in an amount of 1to 6 moles, preferably 2 to 4 moles, per one mole of the compound [III].

When magnesium is used in the above reaction, the reaction is preferablycarried out in the presence of a halogenated compound such as methyliodide or 1,2-dibromoethane or a mixture of such halogenated compoundand iodine. This reaction is preferably carried out at a temperature of-20° to 100° C., especially at a temperature of 50° to 80° C. in thecase of using zinc and at a temperature of -20° to 30° C. in the case ofusing magnesium.

When an amount of 0.01 to 2 moles of a Lewis acid (e.g., zinc bromide,triethylboran, trimethylsilylchloride, magnesium bromide) is used as acatalyst, the reaction is accelerated and the reaction time can beshortened.

The α-halopropionamide compound [II] which is one of the startingcompounds of the present invention is a novel compound and can beprepared by reacting a benzene compound of the formula [IV]: ##STR21##wherein symbols are the same as defined above or a salt thereof, with a2-halogenopropionic acid compound of the formula [V]: ##STR22## whereinL⁰ is the same as defined above, a salt or a reactive derivativethereof.

The reaction of the benzene compound [IV] with the 2-halogenopropionicacid compound [V] can be preferably carried out in an appropriatesolvent in the presence of a dehydrating agent. Examples of thedehydrating agent include carbonyldiimidazole, dicyclohexylcarbodiimide,N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like. Ether,methylene chloride, tetrahydrofuran, acetonitrile and the like arepreferably used as the solvent. The reaction is preferably carried outat a temperature of -30° to 70° C., especially at a temperature of 0° to30° C.

The reaction of the benzene compound [IV] with the reactive derivativeof the 2-halogenopropionic acid compound [V] can be carried out in anappropriate solvent in the presence of an acid acceptor. Examples of thereactive derivative of the 2-halogenopropionic acid compound [V] includethe corresponding acid halide, acid anhydride and the like. Examples ofthe acid acceptor include bases such as an alkali metal hydride, analkali metal, a lower alkyl lithium, phenyllithium, pyridine and adi-lower alkyl aniline. Ether, benzene, dichloromethane, chloroform andthe like are preferably used as the solvent. The reaction is preferablycarried out at a temperature of -80° to 50° C.

The azetidinone compound [I] of the present invention can be suitablyconverted into a desired 1β-methylcarbapenem type antibacterial agent insuch a manner as described in the following lines. That is, a desired1β-methylcarbapenem type antibacterial agent can be prepared, forexample, by reacting the azetidinone compound [I] or a salt thereof withan acetic acid compound of the formula [VI]:

    L.sup.2 --CH.sub.2 --COOR.sup.2                            [VI]

wherein R² is hydrogen atom or an ester residue, and L² is a leavinggroup, or a salt thereof to give a N-substituted azetidinone compound ofthe formula[VII]: ##STR23## wherein symbols are the same as definedabove, subjecting the compound [VII] or a salt thereof to intramolecularcyclization, subjecting the product to esterification to give a1β-methyl-2-oxycarbapenem derivative of the formula [VIII]: wherein agroup of the formula: --OA is an esterified hydroxy group, and othersymbols are the same as defined above, and then converting said1β-methyl-2-oxycarbapenem derivative [VIII] or a salt thereof into adesired 1β-methylcarbapenem type antibacterial agent by a known method,for example, by the method described in Japanese Patent Publication(unexamined) No. 279588 of 1992. For example, a 1β-methylcarbapenemderivative of the formula [X]: ##STR24## wherein R ¹¹ is ahydroxy-substituted lower alkyl group which may be protected, R²¹ is ahydrogen atom or an ester residue and R³ is an organic group, or a saltthereof, may be prepared by carrying out the following three steps inarbitrary orders;

(i) a step of reacting the compound [VIII] or a salt thereof with athiol compound of the formula [IX]:

    H--SR.sup.3                                                [IX]

wherein R³ is the same as defined above, or a salt thereof,

(ii) when R¹ is a protected hydroxy-substituted lower alkyl group, anoptional step for removing the protecting group and

(iii) when R² is an ester residue, an optional step for removing theester residue.

When R² in the acetic acid compound [VI], in the N-substitutedazetidinone compound [VII] or in the 1β-methyl-2-oxycarbapenemderivative [VIII] and R²¹ in the 1β-methylcarbapenem derivative [X] areester residues, examples of such ester residues include those which canbe metabolized or hydrolyzed in the human body or those which can beused as a protecting group of carboxyl group. Examples of the esterresidue which can be metabolized or hydrolyzed in the human body includea group of the formula: --Q--OCOR⁴, --Q--OCO₂ R⁴ or --Q--O--R⁴ (whereinQ is a lower alkylene group, and R⁴ is a lower alkyl group, a cycloalkylgroup, a lower alkenoyl group, a lower alkoxy-lower alkyl group or alower alkanoyloxy-lower alkyl group). More specific examples of suchester residue include a lower alkanoyloxy-lower alkyl group, acycloalkylcarbonyloxy-lower alkyl group, a lower alkenoyloxy-lower alkylgroup, a lower alkoxy-lower alkanoyloxy-lower alkyl group, a loweralkanoyloxy-lower alkoxy-lower alkyl group, a lower alkoxy-lower alkylgroup, a lower alkoxy-lower alkoxy-lower alkyl group, a loweralkoxy-carbonyloxy-lower alkyl group, a lower alkoxy-loweralkoxy-carbonyloxy-lower alkyl group and the like.

On the other hand, examples of the ester residue which can be used as aprotecting group of carboxyl group include any one which can be easilyremoved by a conventional method, for example, a lower alkyl group, alower alkenyl group, a halogeno-lower alkyl group, nitrobenzyl group, alower alkoxy-benzyl group, benzhydryl group and the like.

Examples of the esterified hydroxy group of the formula: --OA includethose which can be easily replaced by the group:

--SR³, for example a di-arylphosphoryloxy (e.g., diphenylphosphoryloxy)or di-lower alkylphosphoryloxy group shown by a formula:

    --OP(O)(OR.sup.0).sub.2

(wherein R⁰ is an aryl group or a lower alkyl group), an unsubstitutedor substituted lower alkylsulfonyloxy group (e.g., methanesulfonyloxygroup, ethanesulfonyloxy group, trifluoromethanesulfonyloxy group), anunsubstituted or substituted arylsulfonyloxy group (e.g.,benzenesulfonyloxy group, toluenesulfonyloxy group), a lower alkanoyloxygroup (e.g., acetoxy group), an arylcarbonyloxy group (e.g., benzoyloxygroup) and the like. Among them, the preferred examples include theesterified hydroxy group such as a di-arylphosphoryloxy group, adi-lower alkylphosphoryloxy group, an unsubstituted or substituted loweralkylsulfonyloxy group, an unsubstituted or substituted arylsulfonyloxygroup and the like.

The organic group shown by R³ in the thiol compound [IX] and the1β-methylcarbapenem derivative [X] include any group which showsantibacterial activity when used as a substituent of a carbapenem typecompound, especially any group used as a substituent in the knowncarbapenem type antibacterial agents, for example, those described inJapanese Patent Publication (unexamined) Nos. 18779 of 1986, 202886 of1985, 5081 of 1986, 49783 of 1990 and 279588 of 1992 and U.S. Pat. No.4194047. Examples of such group include a lower alkyl group, acycloalkyl group, a 6- to 8-membered aryl group, a 4- to 8-memberedaliphatic heterocyclic group, a 4- to 8-membered aromatic heterocyclicgroup and the like. Besides, those groups may have one or moresubstituent(s), and examples of such substituents include a lower alkylgroup, hydroxy group, a lower alkoxy group, a lower alkylamino group,mercapto group, a lower alkylthio group, amidino group, guanidino group,carbamoyl group, thiocarbamoyl group, sulfamoyl group, cyano group,carboxyl group, a lower alkoxy-carbonyl group, an aralkyloxycarbonylgroup, oxo group, a halogen atom, a cycloalkyl group, a 6- to 8-memberedaryl group, a 4- to 8-membered aliphatic heterocyclic group, a 4- to8-membered aromatic heterocyclic group and the like.

The reaction of the azetidinone compound [I] with the acetic acidcompound [VI] can be carried out in an appropriate solvent in thepresence of a base. Examples of the leaving group (L²) include a halogenatom, an acyloxy group and a sulfonyloxy group (e.g.,p-toluenesulfonyloxy group or methanesulfonyloxy group). Examples of thebase include an organic base such as 1,8-diazabicyclo[5.4.0.]undec-7en,an alkali metal compound such as an alkali metal hydride, an alkalimetal hydroxide or an alkali metal carbonate and a metal salt of aminesuch as sodium amide, lithium diisopropylamide and sodiumbis(trimethylsilyl)amide. Tetrahydrofuran, benzene, dichloromethane andthe like may be used as the solvent. The reaction is preferably carriedout at a temperature of -50° to -20° C.

The intramolecular cyclization of the N-substituted azetidinone compound[VII] can be carried out in the presence of a base. Examples of the baseinclude those which are used in the Dieckmann-type reaction, forexample, an alkali metal salt of amine (e.g., sodiumbis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide), an alkalimetal salt of alcohol (e.g., potassium tert-butoxide), an alkali metalhydride (e.g., sodium hydride) and the like. The base may be used in anamount of 1.0 to 3.0 moles, preferably 2.0 to 2.5 moles, per one mole ofthe compound [VII]. Examples of the solvent include tetrahydrofuran,ethylene glycol dimethyl ether, dioxane, toluene, diethyl ether, benzeneand the like. The reaction is preferably carried out at a temperature of-78° to 50° C., especially at a temperature of -60° to 10° C.

It is presumed that the compound having a structure of the formula [XI]:##STR25## wherein symbols are the same as defined above, is produced inthis intramolecular cyclization. The intramolecular cyclization productthus obtained may be isolated from the reaction mixture or subjected tothe subsequent esterification without isolation. However, theintramolecular cyclization and the esterification may be preferablycarried out subsequently in the same solvent without isolating thecyclization product.

The esterification of the intramolecular cyclization product can becarried out by reacting it with an esterifying reagent for hydroxygroup. Examples of the esterifying reagent for hydroxy group include areactive derivative (e.g., a corresponding acid halide, a correspondingacid anhydride) of a di-aryl phosphate (e.g., diphenyl phosphate), adi-lower alkyl phosphate (e.g., diethyl phosphate), an unsubstituted orsubstituted lower alkanesulfonic acid (e.g., methanesulfonic acid,ethanesulfonic acid, trifluoromethanesulfonic acid), an unsubstituted orsubstituted arylsulfonic acid (e.g., benzenesulfonic acid,toluenesulfonic acid), a lower alkanoic acid (e.g., acetic acid) or anarylcarboxylic acid (e.g., benzoic acid). Among them, the preferredesterifying reagents for hydroxy group include the reactive derivative(e.g., a corresponding acid halide, a corresponding acid anhydride) of adi-aryl phosphate, a di-lower alkylphosphate, an unsubstituted orsubstituted lower alkanesulfonic acid or an unsubstituted or substitutedarylsulfonic acid. The esterifying reagent for hydroxy group may be usedin an amount of 1.0 to 4.0 moles, preferably 2.0 to 3.0 moles, per onemole of the compound [VII]. The reaction is preferably carried out at atemperature of -75° to 40° C., especially at a temperature of -60° to10° C.

When the esterification is carried out without isolating theintramolecular cyclization product from the reaction mixture, theintramolecular cyclization and/or the esterification can be carried outin the presence or absence of an acid, but it is preferred to carry outthe reaction in the presence of an acid. Both a Lewis acid and aprotonic acid can be used as the acid, but the Lewis acid may bepreferably used. When the protonic acid is used as the acid in theintramolecular cyclization, it must be added into a reaction vesselafter addition of the base. Examples of the Lewis acid include a metalhalide such as cupric chloride, cuprous iodide, zinc chloride, zinciodide, zinc fluoride, ferric chloride, stannous chloride, stannicchloride and the like, a silyl compound such as a tri-lower alkylhalogenosilane (e.g., trimethylchlorosilane,t-butyldimethylchlorosilane), tetrahalogenosilane (e.g.,tetrachlorosilane) and the like. The Lewis acid may be used in an amountof 0.1 to 2.0 moles, preferably 1.0 to 1.5 moles, per one mole of thecompound [VII]. Examples of the protonic acid include sulfuric acid,p-toluenesulfonic acid, acetic acid, citric acid, hydrochloric acid,phosphoric acid, boric acid and the like. The protonic acid may be usedin an amount of 0.1 to 1.0 mole per one mole of the compound[VII].

When the esterification is carried out in the presence of the acid, theesterifying reagent may be preferably used in an amount of 1.2 to 1.5moles per one mole of the compound [VII].

The reaction of the 1β-methyl-2-oxycarbapenem derivative [VIII] with thethiol compound [IX], the optional step for removing thehydroxy-protecting group of the compound [VIII] in which R ¹ is aprotected hydroxy-substituted lower alkyl group and the optional stepfor removing the ester residue of R² of the compound [VIII] in which R²is an ester residue may be carried out in a conventional method. Forexample, the removal of the hydroxy-protecting group of R¹ or the esterresidue of R² may be performed by hydrolysis, reduction and the like.

The azetidinone compound [I] or a salt thereof can be converted byhydrolysis thereof into an azetidinonepropionic acid compound (anexcellent synthetic intermediate of the carbepenem-type compound) of theformula [XII]: ##STR26## wherein R¹ is the same as defined above, andfurther the compound [XII] or a salt thereof can be converted into thecompound [VIII] or a salt thereof in a conventional method, for example,according to the method described in Japanese Patent Publication(unexamined) No. 123182 of 1982.

The hydrolysis of the compound [I] or a salt thereof can be carried outin a conventional method, but it is preferably carried out in anappropriate solvent in the presence of hydrogen peroxide and an alkalimetal hydroxide. Examples of the solvent include a mixture of water andan organic solvent such as dioxane, tetrahydrofuran, dimethylformamide,methanol and the like, preferably a mixture of water andtetrahydrofuran. Examples of the alkali metal hydroxide include lithiumhydroxide, sodium hydroxide, potassium hydroxide and the like,preferably lithium hydroxide. Hydrogen peroxide may be used in an amountof 1 to 10 moles, preferably 6 to 8 moles, per one mole of the compound[I], and the alkali metal hydroxide may be used in an amount of 1 to 5moles, preferably 2 to 3 moles, per one mole of the compound [I]. It ispreferred to carry out the reaction at a temperature of -10° to 30° C.,especially at a temperature of -5° to 5° C.

The conversion of the compound [XII] or a salt thereof into the compound[VIII] or a salt thereof may be carried out according to the methoddescribed in Japanese Patent Publication (unexamined) No. 188662 of1988.

In the above reactions, the compounds [I], [II], [IV], [V], [VI], [VII],[VIII], [IX], [X], [XI] and [XII] may be also used in the form of anappropriate salt thereof which is suitable for each of the abovecompounds. Examples of such salt include a metal salt such as sodiumsalt, potassium salt and the like; an amine salt such as trialkylaminesalt, pyridine salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, and the like; an inorganic acid addition saltsuch as hydrochloride, hydrobromide, sulfate and the like; and anorganic acid addition salt such as acetate, oxalate, tartrate, fumarate,maleate, benzenesulfonate and the like.

According to the present invention, the azetidinone compound [I] or asalt thereof can be converted into the 1β-methyl-2-oxycarbapenemderivative [VIII] or a salt thereof and the 1β-methylcarbapenemderivative [X] or a salt thereof with retaining the stereo-structure.

Besides, the benzene compound [IV] in which Y is oxygen atom, sulfuratom or an imino group which may have substituent(s) may be preparedaccording to the method described in Journal of the American ChemicalSociety Vol.72, p721 (1950). To say particularly, said compound [IV] maybe prepared by condensing a compound of the formula [XIII]: ##STR27##wherein symbols are the same as defined above, with a compound of theformula [XIV]:

    Z=O                                                        [XIV]

wherein Z is the same as defined above.

Besides, the compound [XIII] in which X is oxygen atom and Y is sulfuratom may be prepared by halogenating a compound of the formula [XV]:##STR28## wherein Ring B is the same as defined above, to give acompound of the formula[XVI]: ##STR29## wherein X² is a halogen atom,and Ring B is the same as defined above, subjecting the compound [XVI]to amidation to give a compound of the formula [XVII]: ##STR30## whereinRing B is the same as defined above, and then reducing the compound[XVII].

Besides, the compound [XIII] in which X is oxygen atom and Y is an iminogroup which may have substituent(s) may be prepared by reacting acompound of the formula [XVIII]: ##STR31## wherein Y¹ is an imino groupwhich may have substituent(s), and other symbols are the same as definedabove, with ammonia.

Besides, the compound [XIII] in which X is sulfur atom and Y is sulfuratom or an imino group which may have substituent(s) may be prepared bysubjecting the compound [XIII] in which X is oxygen atom and Y is sulfuratom or an imino group which may have substituent(s) tothiocarbonylation.

Besides, the benzene compound [IV] in which Y is methylene group may beprepared by reacting the compound of the formula [XIX]: ##STR32##wherein L³ is a halogen atom or hydroxy group, and Ring B is the same asdefined above, with a compound of the formula [XX]:

    HZ--NO.sub.2                                               [XX]

wherein Z is the same as defined above, to give a compound of theformula [XXI]: ##STR33## wherein symbols are the same as defined above,reducing the compound [XXI] to give a compound of the formula [XXII]:##STR34## wherein symbols are the same as defined above, reacting theproduct with a compound of the formula [XXIII]: ##STR35## wherein X isthe same as defined above, and then subjecting the product tointramolecular cyclization.

The condensation reaction of the compound [XIII] with the compound [XIV]may be carried out in an appropriate solvent in the presence of an acid.Examples of the acid include an organic acid (e.g., p-toluenesulfonicacid) and an inorganic acid (e.g., sulfuric acid, hydrochloric acid).Examples of the preferred solvent include an organic solvent which has aboiling point higher than water (e.g., toluene). It is preferred tocarry out the reaction at a temperature of 50 to 180° C., especially ata temperature of 80° to 130° C.

The halogenation of the compound [XV] may be carried out by treating thecompound with a halogenating agent in an appropriate solvent

Examples of the halogenating agent include thionyl chloride, phosphorusoxychloride and the like, and examples of the solvent include an inertone such as toluene. It is preferred to carry out the reaction at atemperature of 20° to 120° C., especially at a temperature of 70° to 80°C.

The amidation of the compound [XVI] may be carried out by treating thecompound with ammonia in an appropriate solvent. Ammonia may bepreferably used in the form of aqueous ammonia, and examples of thepreferred solvent include a solvent which can be mixed with water, forexample, ethers such as dioxane and alcohols such as ethanol. It ispreferred to carry out the reaction at a temperature of 30° to 120° C.,especially at a temperature of 80° to 90° C.

The reduction of the compound [XVII] may be carried out in anappropriate solvent in the presence of zinc and an acid catalyst.Examples of preferred acid catalyst include an inorganic acid such ashydrochloric acid, and examples of the preferred solvent include etherssuch as dioxane. It is preferred to carry out the reaction at atemperature of 40° to 100° C., especially at a temperature of 60° to 70°C.

The reaction of the compound [XVIII] with ammonia may be carried out inan appropriate solvent. Ammonia may be used in the form of aqueousammonia, and examples of the preferred solvent include water, etherswhich can be mixed with water (e.g., dioxane) and alcohols (e.g.,ethanol). It is preferred to carry out the reaction at a temperature of0° to 100° C., especially at a temperature of 25° to 80° C.

The thiocarbonylation of the compound [XIII] in which X is oxygen atomand Y is sulfur atom or an imino group which may have substituent(s) maybe carried out by treating the compound with a thiocarbonylation agentin an appropriate solvent. Examples of the preferred thiocarbonylationagent include 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide,2,4-dimethyl-1,3-dithia-2,4-diphosphetane-2,4-disulfide, phosphoruspentasulfide and the like. Examples of the solvent include any inert onesuch as dimethoxyethane, pyridine, xylene, toluene, benzene and thelike. It is preferred to carry out the reaction at a room temperature orunder heating, especially at a temperature of 60° to 100° C.

The reaction of the compound [XIX] with the compound [XX] may be carriedout in an appropriate solvent in the presence of an acid acceptor.Examples of the acid acceptor include an alkali metal hydride, an alkalimetal, an alkali metal fluoride, a lower alkyl-lithium, phenyllithiumand the like. Examples of the solvent include dimethylformamide,tetrahydrofuran and the like. It is preferred to carry out the reactionunder cooling or with heating, for example, at a temperature of 30° to120° C., especially at a temperature of 30° to 80° C.

The reduction of the compound [XXI] may be carried out in an appropriatesolvent either by treating the compound with a reducing agent or bycatalytic hydrogenation.

In the case of treating it with a reducing agent, examples of thereducing agent include a metal hydride such as lithium aluminum hydride,sodium bis (methoxyethoxy)aluminum hydride, sodium borohydride and thelike. Examples of the solvent include ethers such as tetrahydrofuran,diethyl ether, dioxane and the like. It is preferred to carry out thereaction at a temperature of 0° to 100° C., especially at a temperatureof 30° to 60° C.

On the other hand, in the case of catalytic hydrogenation, preferredexamples of the catalyst include palladium-carbon, palladium-black andthe like. Examples of the solvent include alcohols such as methanol,ethanol and the like. It is preferred to carry out the reaction at atemperature of 0° to 70° C., especially at a temperature of 20° to 30°C.

The reaction of the compound [XXII] with the compound [XXIII] may becarried out in an appropriate solvent in the presence or absence of anacid acceptor. Examples of the acid acceptor include a base such as analkali metal, an alkali metal hydride, an alkali metal hydroxide, analkali metal alkoxide, an alkali earth metal hydroxide,an alkali earthmetal alkoxide, a lower alkyl-lithium, phenyllithium, pyridine, di-loweralkylaniline and the like. Examples of the solvent includedimethylformamide, tetrahydrofuran, ether and the like. It is preferredto carry out the reaction at a temperature of 0° to 100° C., especiallyat a temperature of 20° to 50° C. The subsequent intramolecularcyclization of the product may be carried out in the presence of adehydrating agent. Examples of the dehydrating agent includepolyphosphoric acid, phosphorus oxychloride and the like. Examples ofthe solvent include an inert one such as toluene, benzene and the like.It is preferred to carry out the reaction at a temperature of 50° to150° C., especially at a temperature of 80° to 130° C.

Throughout the specification and claims, the term "lower alkyl group","lower alkylene group" and "lower alkoxy group" include a straight-chainor branch-chain alkyl group of 1 to 6, preferably 1 to 4 carbon atoms, astraight-chain or branch-chain alkylene group of 1 to 6, preferably 1 to4 carbon atoms and a straight-chain or branch-chain alkoxy group of 1 to6, preferably 1 to 4 carbon atoms, respectively. And the term "loweralkanoyl group" and "lower alkenyl group" include a straight-chain orbranch-chain alkanoyl group of 2 to 8, preferably 2 to 6 carbon atomsand a straight-chain or branch-chain alkenyl group of 2 to 8, preferably2 to 6 carbon atoms, respectively. Further, the term "lower alkenoylgroup" and "cycloalkyl group" include a straight-chain or branch-chainalkenoyl group of 3 to 8, preferably 3 to 6 carbon atoms and acycloalkyl group of 3 to 8, preferably 4 to 7 carbon atoms,respectively.

EXAMPLE 1

A solution of 89.1 ml of 2-bromopropionyl bromide in 95 ml of methylenechloride and a solution of 61.13 g of pyridine in 95 ml of methylenechloride are added dropwise to a suspension of 140 g ofspiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one in 190 ml ofmethylene chloride under nitrogen atmosphere at -5° C. during about 45minutes. Then the mixture is stirred at a room temperature for 6 hours.The reaction mixture is poured into 500 ml of water and the mixture isextracted with methylene chloride. The extract is washed, dried andevaporated to remove the solvent and the residue obtained iscrystallized from methanol and the crystals are collected by filtrationto obtain 197.3 g of3-(2-bromopropionyl)-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one.

m.p.: 74°-76° C.

EXAMPLES 2 to 10

The corresponding starting compounds and 2-bromopropionyl bromide aretreated in the same manner as described in Example 1 to obtain thecompounds listed in Tables 1 and 2.

                                      TABLE 1                                     __________________________________________________________________________     ##STR36##                                                                    Ex.                                    Physical properties,                   No.                                                                              Z.sup.1   Z.sup.2   Y    Ring B     etc.                                   __________________________________________________________________________    2  CH.sub.3  CH.sub.3  O                                                                                   ##STR37## syrup                                  3  n-C.sub.4 H.sub.9                                                                       n-C.sub.4 H.sub.9                                                                       O                                                                                   ##STR38## syrup                                  4  n-C.sub.15 H.sub.31                                                                     n-C.sub.15 H.sub.31                                                                     O                                                                                   ##STR39## syrup                                      ##STR40##                                                                               ##STR41##                                                                              O                                                                                   ##STR42## m.p. 114-115° C.                6  CH.sub.3  CH.sub.3  CH.sub.2                                                                            ##STR43## syrup*                                 __________________________________________________________________________     *: NMR date of the compound of Example 6                                      NMR (CDCl.sub.3)δ: 1.68(3H, d), 1.82(3H, s), 2.05(3H, d, J=7.5Hz),      3.10(2H, s), 3.72(3H, s), 5.22(1H, q, J=7.5Hz), 6.90(1H, d, J=9Hz),           7.55(1H, d, J=3Hz, 9Hz), 7.88(1H, d, J=3Hz)                              

                  TABLE 2                                                         ______________________________________                                         ##STR44##                                                                    Ex.                                                                           No.   Y       Ring B        Physical properties, etc.                         ______________________________________                                        7     S                                                                                      ##STR45##    colorless syrup*                                  8     O                                                                                      ##STR46##    m.p. 89-91° C.                             9     O                                                                                      ##STR47##    m.p. 99-100° C.                            10    O                                                                                      ##STR48##    m.p. 111-112° C.                           ______________________________________                                         *: NMR date of the compound of Example 7                                      NMR (CDCl.sub.3)δ: 1.1-2.6(10H, m), 1.94(3H, d, J=6.6Hz), 4.87(1H,      q, J=6.6Hz), 7.2-7.4(2H, m), 7.48(1H, t, J=7.5Hz), 8.11(1H, d, J=7.7Hz)  

EXAMPLE 11

1.0 g of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2azetidinone, 1.8g of3-(2-bromopropionyl)-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-oneand 0.68 g of zinc powders are added to 15 ml of tetrahydrofuran and themixture is refluxed for 30 minutes. After cooling, the reaction mixtureis poured into 0.2M phosphate buffer (pH 7.0) and the mixture isextracted with methylene chloride. The extract is washed, dried andevaporated to remove the solvent. The residue is purified by silica gelcolumn chromatography (solvent; hexane:ethyl acetate =3:1)to obtain 1.3g of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one.

m.p.: 154°-155° C.

EXAMPLES 12 to 20

The corresponding starting compounds and (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxy)ethyl]-2-azetidinone aretreated in the same manner as described in Example 11 to obtain thecompounds listed in Tables 3 and 4.

                                      TABLE 3                                     __________________________________________________________________________     ##STR49##                                                                    Ex.                                    Physical properties,                   No.                                                                              Z.sup.1   Z.sup.2   Y    Ring B     etc.                                   __________________________________________________________________________    12 CH.sub.3  CH.sub.3  O                                                                                   ##STR50## m.p. 133-134° C.                13 n-C.sub.4 H.sub.9                                                                       n-C.sub.4 H.sub.9                                                                       O                                                                                   ##STR51## syrup                                  14 n-C.sub.15 H.sub.31                                                                     n-C.sub.15 H.sub.31                                                                     O                                                                                   ##STR52## syrup                                  15                                                                                ##STR53##                                                                               ##STR54##                                                                              O                                                                                   ##STR55## syrup                                  16 CH.sub.3  CH.sub.3  CH.sub.2                                                                            ##STR56## syrup*                                 __________________________________________________________________________     TBS represents tbutyidimethylsilyl group (hereinafter the same)               *: NMR date of the compound of Example 16                                     NMR (CDCl.sub.3)δ: 0.07(6H, s), 0.89(9H, s), 1.22(3H, d, J=6Hz),        1.28(3H, d, J=7.5Hz), 1.72(3H, s), 1.80(3H, s), 3.10(2H, s), 3.20(1H, m),     3.50-3.60(1H, m), 3.72(3H, s), 4.02-4.08(1H, m), 4.10-4.25(1H, m),            5.95(1H, s), 6.93(1H, d, J=9Hz), 7.53(1H, dd, J=3Hz, 9Hz), 7.92(1H, d,        J=3Hz)                                                                   

                  TABLE 4                                                         ______________________________________                                         ##STR57##                                                                    Ex.                                                                           No.   Y       Ring B        Physical properties, etc.                         ______________________________________                                        17    S                                                                                      ##STR58##    syrup*                                            18    O                                                                                      ##STR59##    syrup                                             19    O                                                                                      ##STR60##    m.p. 173-175° C.                           20    O                                                                                      ##STR61##    m.p. 155-158° C.                           ______________________________________                                         *: NMR data of the compound of Example 17                                     NMR (CDCl.sub.3) δ: 0.08(3H, s), 0.09(3H, s), 0.86(9H, s), 1.22(3H,     d, J=6.3), 1.26(3H, d, J=7.2Hz), 1.5-2.5(10H, m), 3.1-3.2(1H, m),             3.2-3.4(1H, m), 4.11(1H, dd, J=2.3Hz, 4.0Hz), 4.22(1H, dt, J=6.2Hz,           10.7Hz), 5.92(1H, brs), 7.26(1H, d, J=7.3Hz), 7.47(1H, dt, J=1.5Hz,           7.5Hz), 8.13(1H, dd, J=1.4Hz, 8.4Hz)                                     

EXAMPLE 21

(1) 16.2 ml of 1M sodium bis(trimethylsilyl)amide solution (solvent:tetrahydrofuran) are added to a mixture of 7 g of 3-{(2R)-2-[(3R,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-oneand 2.89 g of allyl bromoacetate in 35 ml of tetrahydrofuran at -60° C.and the mixture is warmed to a temperature of -30 ° C. during one hour.The reaction mixture is poured into a mixture of water and ethyl acetateand the ethyl acetate layer is washed, dried and evaporated to removethe solvent. The residue is purified by silica gel column chromatography(solvent; hexane:ethyl acetate=20:1-5:1) to obtain 8.03 g of3-{(2R)-2-[(3S,4R)-1-allyloxycarbonylmethyl-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one as syrup.

(2) A solution of 1.2 g of 3-{(2R)-2-[(3S,4R)-1-allyloxycarbonylmethyl-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-onein 6 ml of tetrahydrofuran is added dropwise to 4.4 ml of 1M sodiumbis(trimethylsilyl)amide solution (solvent:tetrahydrofuran) at atemperature from -20° C. to -30° C. during one minute. 261 mg oftrimethylsilyl chloride are added thereto at -50° C. and the mixture isstirred for 2 minutes. Then, 645 mg of diphenylphosphoryl chloride areadded thereto at -50 ° C. and the mixture is stirred for 2 hours at 0°C. The reaction mixture is poured into 50 ml of 0.2M phosphate buffer(pH 7.0) and the mixture is extracted with ethyl acetate. The extract iswashed, dried and evaporated to remove the solvent. Isopropyl ether isadded to the residue and the resulting precipitates of 355 mg ofspiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one are removedby filtration. The filtrate is condensed to obtain 1.04 g of (1R, 5R,6S)-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-1-methyl-2-diphenylphosphoryloxy-carbapen-2-em-3-carboxylicacid.allyl ester as syrup.

EXAMPLE 22

To a solution of 500 mg of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-onein 20 ml of a mixture of tetrahydrofuran and water are added 0.9 ml of30% aqueous hydrogen peroxide and 84 mg of lithium hydroxide in thisorder, and the mixture is stirred at the same temperature for one hour.The pH of the mixture is adjusted to about 10 by adding dropwise 5 ml of1.5N aqueous sodium sulfite at the same temperature and tetrahydrofuranis removed under reduced pressure. The precipitated crystals are removedby filtration and the aqueous layer of the filtrate is washed with 20 mlof chloroform. 10 ml of 10% hydrochloric acid are added thereto and thepH of the mixture is adjusted to about one. The aqueous layer isextracted with 30 ml of ethyl acetate. The ethyl acetate layer is driedand then evaporated under reduced pressure to give the crude product.The product is recrystallized from a mixture of ethyl acetate and hexaneto obtain 216 mg of (2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionicacid.

m.p.: 146°-147° C.

EXAMPLE 23

A mixture of 10 ml of tetrahydrofuran and a small amount of iodine isadded to 437 mg of magnesium piece at a room temperature and 0.75 g of1,2-dibromoethane are added dropwise thereto with stirring. When theexothermic reaction starts and the mixture begins to reflux, a solutionof 1.51 g of 1,2-dibromoethane in 3 ml of tetrahydrofuran is addeddropwise thereto. Then, the mixture is refluxed for 30 minutes. Themixture is cooled to a temperature of 5° C. and to this cooled liquid isadded dropwise a mixture of 1.15 g of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-azetidinone and2.11 g of3-(2-bromopropionyl)-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-onein 5 ml of tetrahydrofuran. Then, the mixture is stirred at 10° C. forone hour. 60 ml of aqueous saturated ammonium hydrochloride are addedthereto and the mixture is extracted with ethyl acetate. The extract iswashed, dried and evaporated to remove the solvent. The residue ispurified by silica gel column chromatography (solvent; hexane:ethylacetate =6:1-3:1) to obtain 1.61 g of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one.

m.p.: 154°-155° C.

EXAMPLES 24 to 33

The corresponding starting compounds are treated in the same manner asdescribed in Example 1 to obtain the compounds listed in Table 5.Further the compounds listed in Table 5 and (3R,4R)-4-acetoxy-3-[(R)-t-butyldimethylsilyloxy)ethyl]-2-azetidinone aretreated in the same manner as described in Example 11 to obtain thecompounds listed in Table 6.

                  TABLE 5                                                         ______________________________________                                         ##STR62##                                                                    Ex.                                                                           No.       Z.sup.1 Z.sup.2     X   Y                                           ______________________________________                                        24        CH.sub.3                                                                              CH.sub.3    S   S                                           25        (CH.sub.2).sub.4                                                                              S     S                                             26        (CH.sub.2).sub.5                                                                              O                                                                                    ##STR63##                                    27        n-C.sub.4 H.sub.9                                                                     n-C.sub.4 H.sub.9                                                                         O                                                                                  ##STR64##                                  28        (CH.sub.2).sub.5                                                                              O     CH.sub.2                                      ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                         ##STR65##                                                                    Ex.                                                                           No.       Z.sup.1 Z.sup.2     X   Y                                           ______________________________________                                        29        CH.sub.3                                                                              CH.sub.3    S   S                                           30        (CH.sub.2).sub.4                                                                              S     S                                             31        (CH.sub.2).sub.5                                                                              O                                                                                    ##STR66##                                    32        n-C.sub.4 H.sub.9                                                                     n-C.sub.4 H.sub.9                                                                         O                                                                                  ##STR67##                                  33        (CH.sub.2).sub.5                                                                              O     CH.sub.2                                      ______________________________________                                    

Reference example 1

A mixture of 20 g of dibutylketone, 19.3 g of salicylamide and 2.7 g ofp-toluenesulfonic acid monohydrate is added to 300 ml of toluene and themixture is refluxed overnight by making use of a dehydrator of DeanStark. After cooling, the reaction mixture is washed, dried andevaporated to remove the solvent. The residue is purified by silica gelcolumn chromatography (solvent; hexane:ethyl acetate =95:5) to obtain 34g of 2,2-dibutyl-4-oxo-2,3-dihydro-4H-1,3-benzoxazine as a yellow oil.

Reference examples 2 to 6

The corresponding starting compounds [XIII] and the correspondingstarting compounds [XIV] are treated in the same manner as described inReference example 1 to obtain the compounds listed in Table 7.

                                      TABLE 7                                     __________________________________________________________________________     ##STR68##                                                                    Ref.                                                                          Ex.                                                                           No.                                                                              Z.sup.1   Z.sup.2   Ring B   Physical properties, etc.                     __________________________________________________________________________    2  n-C.sub.15 H.sub.31                                                                     n-C.sub.15 H.sub.31                                                                      ##STR69##                                                                             yellow oil                                        ##STR70##                                                                               ##STR71##                                                                               ##STR72##                                                                             m.p. 159-161° C.                       4  (CH.sub.2).sub.5                                                                                   ##STR73##                                                                             m.p. 168-170° C.                       5  (CH.sub.2).sub.5                                                                                   ##STR74##                                                                             m.p. 175-177° C.                       6  (CH.sub.2 ).sub.5                                                                                  ##STR75##                                                                             m.p. 193-195° C.                       __________________________________________________________________________

Reference example 7

(1) 12.5 ml of thionylchloride are added dropwise to a solution of 25.0g of 2,2'-dithiodibenzoic acid in a mixture of 120 ml of toluene and 0.5ml of dimethylformamide at a room temperature. The mixture is warmed toa temperature of 70° to 80° C. and then stirred at the same temperatureovernight. After 20 hours, the crystals are collected by filtration toobtain 14.9 g of 2,2'-dithiodibenzoyl chloride as colorless crystal.

m.p.:140°-141° C.

(2) 20 ml of aqueous ammonia are added to a suspension of 7.03 g of2,2'-dithiodibenzoyl chloride in 20 ml of dioxane at a room temperature.The mixture is warmed to a temperature of 80° to 90° C. and stirred for5 hours at the same temperature. The mixture is cooled to a roomtemperature to give 4.8 g of 2,2'-dithiodibenzoylamide as colorlesscrystal.

Yield: 77% m.p.: 249°-250° C.

(3) 41 ml of 2N hydrochloric acid are added dropwise to a suspension of4.14 g of 2,2'-dithiodibenzoylamide and 2.5 g of zinc powders in 70 mlof dioxane. The mixture is warmed to a temperature of 60°-70° C. andstirred for 4 hours at the same temperature. The reaction mixture ispoured into 50 ml of water and the mixture is extracted with ethylacetate. The ethyl acetate layer is washed, dried and evaporated underreduced pressure to remove the solvent. A mixture of 5.64 ml ofcyclohexanone and 1.03 g of p-toluenesulfonic acid monohydrate is addedto a solution of the above-obtained residue in toluene and the mixtureis refluxed for 40 minutes by making use of a dehydrator of Dean Stark.After cooling to a room temperature, the reaction mixture is condensedunder reduced pressure and methanol is added thereto. The precipitatesare collected by filtration to obtain 3.05 g ofspiro[2,3-dihydro-4H-1,3-benzothiazine-2,1'-cyclohexan]-4-one ascolorless crystal.

m.p.: 193°-195° C.

Reference example 8

(1) 10.0 g of N-methylisatic acid are added gradually to 140 ml of waterat a room temperature and 9.6 g of aqueous ammonia are added dropwisethereto. The mixture is warmed to a temperature of 80° C. during 45minutes and ethanol is added thereto until the reaction mixture becomescolorless. Then, the reaction mixture is cooled to a room temperatureand the precipitated crystals are collected by filtration to obtain 7.11g of 2-carbamoyl-N-methylaniline as colorless crystal.

Yield: 84% m.p.: 155°-156° C.

(2) A mixture of 6.9 ml of cyclohexanone and 633 mg of p-toluenesulfonicacid monohydrate is added to a solution of 5.00 g of the above-obtainedproduct in toluene and the mixture is refluxed with dehydration bymaking use of a dehydrator of Dean Stark for one hour. After cooling toa room temperature, the precipitated crystals are collected byfiltration and washed with methanol to obtain 6.32 g of spiro[1-methyl-1,2,3,4-tetrahydroquinazoline-2,1'-cyclohexan]-4-one as colorlesscrystal.

Yield: 83% m.p.: 183°-185° C.

Reference example 9

A mixture of 11.5 ml of 5-oxononane and 633 mg of p-toluenesulfonic acidmonohydrate is added to a solution of 5.00 g of the product obtained inReference example 8-(1) in toluene, and the mixture is refluxed for 30minutes by making use of a dehydrator of Dean Stark. After cooling to aroom temperature, the mixture is condensed under reduced pressure andthe residue obtained is purified by silica gel column chromatography(solvent; chloroform:methanol=100:1) to obtain 9.16 g of1-methyl-2,2-dibutyl-4-oxo-1,2,3,4-tetrahydroquinazoline as yellowcrystal.

Yield: 100% m.p.: 77-78° C.

Reference example 10

Nitrocyclohexane and benzylbromide are subjected to condensationreaction in the presence of sodium hydride to obtain1-benzyl-1-nitrocyclohexane. The product is reduced with lithiumaluminum hydride to obtain 1-benzyl-1-aminocyclohexane. The product isreacted with methyl chloroformate to obtain1-benzyl-1-methoxycarbonylaminocyclohexane, and the product is subjectedto intramolecular cyclization in the presence of phosphorous oxychlorideto obtain spiro[1,2,3,4-tetrahydroisoquinoline-2,1'-cyclohexan]-1-one.

Reference example 11

(1) A solution of 9.6 g of ethoxycarbonyl chloride in 25 ml of ether isadded dropwise to a solution of 30 g of1-(2-amino-2-methylpropyl)-4-methoxybenzene in 300 ml of ether underice-cooling. Then, a solution of 9.6 g of ethoxycarbonyl chloride in 25ml and a solution of 8 g of sodium hydroxide in 50 ml of water are addeddropwise thereto. After addition, the mixture is stirred for one hourand water is added thereto. The ether layer is removed therefrom and theaqueous layer is extracted with ether twice. A mixture of the etherlayer and the extract is dried and evaporated to remove the solvent. Theresidue is purified by column chromatography to obtain 29.1 g of1-[2-(N-ethoxycarbonyl)amino-2-methylpropyl]-4-methoxybenzene as an oil.

NMR (CDCl₃) δ: 1.63(6H, s), 3.12(2H, s), 3.72(3H, s), 6.70-7.10(4H, m),6.7-7.1(4H, m)

(2) 10 g of the above-obtained product are added to 100 m ofpolyphosphoric acid and the mixture is stirred at a room temperature for30 minutes. Then, the mixture is gradually warmed to a temperature of100° C. and stirred at the same temperature. After cooling to a roomtemperature, 300 ml of water are added thereto and the mixture isextracted with chloroform. The extract is dried and evaporated to removethe solvent. The residue is purified by column chromatography to obtain5.43 g of 1-oxo-3,3-dimethyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline asan oil.

NMR (CDCl₃) δ: 1.62(6H, s), 3.10(2H, s), 3.72(3H, s), 6.90(1H, d, J=9Hz), 7.45(1H, dd, J=3 Hz, 9 Hz), 7.85(1H, d, J=3 Hz)

THE EFFECTS OF THE INVENTION

According to the present invention, the azetidinone compound [I] or asalt thereof can be prepared stereoselectively. Said azetidinonecompound [I ] is a useful synthetic intermediate of the1β-methylcarbapenem derivative, [X] having an antibacterial activitybecause the compound [I] has the partial skeleton (i.e., supportinggroup) of the formula: ##STR76## wherein symbols are the same as definedabove, which is suitable for preparing the 1β-methylcarbapenem skeleton.To say more particularly, the compound [II] or a salt thereof can beconverted into the compound [I] or a salt thereof with highstereoselectivity by reacting it with the compound [III], and hence anoptical resolution must not be required and the expensive compound [III]can be used efficiently.

Moreover, the compound [I] or a salt thereof can be easily convertedinto the compound [XII] or a salt thereof which is an importantintermediate of the 1β-methylcarbapenem derivative by hydrolysis becausethe compound [I] has the 1'-β-methyl group at the 4-position of theazetidinone skeleton.

Further, after the conversion of the compound [I] or a salt thereof intothe compound [VII] or a salt thereof, the thus-obtained compound [VII]can be converted into the compounds [XI] or a salt thereof and [VIII] ora salt thereof by intramolecular cyclization without activating theside-chain group at the 4-position of the azetidinone skeleton bychemical modification.

Furthermore, the supporting group of the present invention can berecovered as the compound [IV] or a salt thereof in the intramolecularcyclization, and therefore, the compound [I] or a salt thereof is usefulas a synthetic intermediate of the 1β-methylcarbapenem derivative [X] ora salt thereof from either an operational or economical point of view.

On the other hand, the α-halopropionamide compound [II] or a saltthereof can be readily prepared. For example, the compound [II] in whichboth X and Y are oxygen atoms and the Ring B is unsubstituted benzenering can be prepared from commercially available salicylamide by twosteps.

Therefore, according to the present invention, the 1β-methylcarbapenemderivative [X] or a salt thereof can be easily prepared in an industrialscale because it is not necessary to perform the optical resolution, touse the expensive Lewis acid such as tin triflate or boron triflate andto activate the side-chain group at the 4-position of the azetidinoneskeleton by chemical modification.

What we claim is:
 1. An azetidinone compound of the formula [I]:##STR77## wherein Ring B is a benzene ring which may be substituted byone to four group(s) selected from the group consisting of a halogenatom, a lower alkyl group, a lower alkoxy group and an aryl group; R¹ isa hydroxy-substituted lower alkyl group which may be protected; X isoxygen atom or sulfur atom; Y is oxygen atom, sulfur atom, methylenegroup or an imino group which may be substituted by a lower alkyl groupor an acyl group selected from the group consisting of a lower alkanoylgroup, a lower alkoxycarbonyl group, a phenylcarbonyl group or aphenyl-lower alkoxycarbonyl group; and Z is a methylene group which maybe substituted by one to two group(s) selected from the group consistingof a C₃₋₇ alkylene group, a C₁₋₂₀ alkyl group, a C₄₋₇ cycloalkyl group(said alkylene group, alkyl group and cycloalkyl group further may havesubstituent(s) selected from the group consisting of a lower alkylgroup, a lower alkoxy group, a halogen atom and an amino group which maybe protected), an aryl group, an aralkyl group and a heterocyclic groupwhich is a 4-to-7-membered heterocyclic group containing oxygen atom,nitrogen atom or sulfur atom as a hetero atom; or a salt thereof.
 2. Thecompound according to claim 1, wherein Z is a methylene group which maybe substituted by one to two group(s) selected from the group consistingof a C₃₋₇ alkylene group, a C₁₋₂₀ alkyl group, a C₄₋₇ cycloalkyl group(said alkylene group, alkyl group and cycloalkyl group further may havesubstituent(s) selected from the group consisting of a lower alkylgroup, a lower alkoxy group, a halogen atom and an amino group which maybe protected), an aryl group and an aralkyl group.
 3. The compoundaccording to claim 1, wherein Ring B is a benzene ring which may besubstituted by a halogen atom, a lower alkyl group or a lower alkoxygroup, Y is oxygen atom, sulfur atom, methylene group or an imino groupsubstituted by a lower alkyl group, and Z is a methylene group which maybe substituted by one to two group(s) selected from the group consistingof a C₃₋₇ alkylene group, a C₁₋₂₀ alkyl group and an aralkyl group. 4.The compound according to claim 3, wherein Ring B is an unsubstitutedbenzene ring, X is oxygen atom, Y is oxygen atom, and Z is a methylenegroup substituted by a C₃₋₇ alkylene group, a di(C₁₋₂₀alkyl)-substituted methylene group or a di(phenyl-loweralkyl)-substituted methylene group.
 5. The compound according to claim4, wherein Z is pentamethylene-substituted methylene group ordibutyl-substituted methylene group.
 6. The compound according to claim2 wherein the 3-position of the azetidinone skeleton has Sconfiguration.
 7. 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-Butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one.8. The compound according to claim 3, wherein the 3-position of theazetidinone skeleton has S configuration.
 9. The compound according toclaim 4, wherein the 3-position of the azetidinone skeleton has Sconfiguration.
 10. The compound according to claim 5, wherein the3-position of the azetidinone skeleton has S configuration.
 11. Thecompound according to claim 1, wherein said heterocyclic group is anunsubstituted 4-to-7-membered heteromonocyclic group containing oneoxygen atom, one nitro atom or one sulfur atom.
 12. The compoundaccording to claim 1, wherein the 3-position of the azetidinone skeletonhas S configuration.
 13. The compound according to claim 2, wherein RingB is a benzene ring which may be substituted by a halogen atom, a loweralkyl group or a lower alkoxy group, Y is oxygen atom, sulfur atom,methylene group or an imino group substituted by a lower alkyl group,and Z is a methylene group which may be substituted by one to twogroup(s) selected from the group consisting of a C₃₋₇ alkylene group, aC₁₋₂₀ alkyl group and an aralkyl group.
 14. The compound according toclaim 13, wherein Ring B is an unsubstituted benzene ring, X is oxygenatom, Y is oxygen atom, and Z is a methylene group substituted by a C₃₋₇alkylene group, a di(C₁₋₂₀ alkyl)-substituted methylene group or adi(phenyl-lower alkyl)-substituted methylene group.
 15. The compoundaccording to claim 14, wherein Z is pentamethylene-substituted methylenegroup or dibutyl-substituted methylene group.
 16. The compound accordingto claim 11, wherein the 3-position of the azetidinone skeleton has Sconfiguration.
 17. The compound according to claim 13, wherein the3-position of the azetidinone skeleton has S configuration.
 18. Thecompound according to claim 14, wherein the 3-position of theazetidinone skeleton has S configuration.
 19. The compound according toclaim 15, wherein the 3-position of the azetidinone skeleton has Sconfiguration.